Endogenous Fusarium Endophthalmitis after Bone Marrow Transplant: A Case Report and Literature Review

Purpose: We aim to present a case of disseminated fusariosis that occurred in the setting of immunosuppression and presented with bilateral endogenous endophthalmitis, along with a literature review of Fusarium endophthalmitis, highlighting management strategies. Observation: A 70-year-old male with acute myeloid leukemia who had recently undergone a bone marrow transplant noted bilateral floaters and decreased vision. He was found to have bilateral Fusarium endophthalmitis, with subsequent evidence of fungemia and fusariosis in his skin and joints. Despite aggressive local and systemic treatment, he succumbed to the disease. Endophthalmitis was initially stabilized with pars plana vitrectomy and intravitreal amphotericin and voriconazole until the patient transitioned to comfort measures. A review of 31 cases demonstrates that outcomes are poor and that the disease must be treated aggressively, often both systemically and surgically. Conclusion: This case highlights the recalcitrance of Fusarium bacteremia and Fusarium endophthalmitis.


Introduction
Although ubiquitous in the environment as a plant pathogen, Fusarium does not commonly result in systemic fungal infection or enter the eye to cause endophthalmitis [1].When present, Fusarium endophthalmitis more commonly occurs exogenously after inoculation from trauma, invasion into the eye from keratitis, or after cataract surgery.Often, in these cases, aggressive treatment is required, and prognosis remains poor despite multifaceted local, surgical, and systemic treatment [2][3][4][5].This report illustrates a case of bilateral endogenous Fusarium endophthalmitis in an immunocompromised patient, highlighting the complex multidisciplinary care these rare cases require.

Case Report
A 70-year-old male with acute myeloid leukemia (AML) presented for a mismatched, unrelated donor bone marrow transplant (BMT).He had previously been treated with three cycles of chemotherapy, including two rounds of intrathecal chemotherapy for presumed central nervous system disease.While the central nervous system disease showed improvement, the patient had residual bone marrow involvement.
Despite a hospital course complicated by neutropenic fever, acute pulmonary edema, new-onset atrial fibrillation, and clostridium difficile colonization, his bone marrow transplant team felt optimistic one month after his BMT that his immune system was recovering and that his disease may have been cured.Throughout this first month after BMT, he was on antibacterial, antiviral, and antifungal agents for prophylaxis: oral levofloxacin for neutropenic fever, oral acyclovir for herpes simplex virus (HSV) and varicella-zoster virus (VZV), oral letermovir for cytomegalovirus (CMV), oral trimethoprim/sulfamethoxazole for pneumocystis jiroveci pneumonia, and oral isovuconazole for fungal prophylaxis.
It was at this time, one month following BMT, that the patient noted one week of bilateral floaters and decreased vision.An ophthalmology consult was requested.On exam, his visual acuity was counting fingers from two feet in both eyes with normal intraocular pressures.He had mild temporal conjunctival injection in the left eye but an otherwise normal anterior segment exam.The dilated fundus exam was notable for mild vitreous haze bilaterally, numerous foci of elevated, subretinal lesions, and overlying hemorrhage in the macula of each eye.Ocular ultrasonography (Figure 1) confirmed the presence of subretinal masses and vitreous debris bilaterally, without retinal detachment.and that his disease may have been cured.Throughout this first month after BMT, he was on antibacterial, antiviral, and antifungal agents for prophylaxis: oral levofloxacin for neutropenic fever, oral acyclovir for herpes simplex virus (HSV) and varicella-zoster virus (VZV), oral letermovir for cytomegalovirus (CMV), oral trimethoprim/sulfamethoxazole for pneumocystis jiroveci pneumonia, and oral isovuconazole for fungal prophylaxis.It was at this time, one month following BMT, that the patient noted one week of bilateral floaters and decreased vision.An ophthalmology consult was requested.On exam, his visual acuity was counting fingers from two feet in both eyes with normal intraocular pressures.He had mild temporal conjunctival injection in the left eye but an otherwise normal anterior segment exam.The dilated fundus exam was notable for mild vitreous haze bilaterally, numerous foci of elevated, subretinal lesions, and overlying hemorrhage in the macula of each eye.Ocular ultrasonography (Figure 1) confirmed the presence of subretinal masses and vitreous debris bilaterally, without retinal detachment.Due to concern for recurrent or widespread malignancy, magnetic resonance imaging (Figure 2) and a lumbar puncture were performed, neither of which showed evidence of neoplasia.The patient received a vitreous tap and intravitreal injection of voriconazole (100 mcg/0.1 mL), vancomycin (1 mg/0.1 mL), and ceftazidime (2.25 mg/0.1 mL) in both eyes.After five days, the culture began to grow fungi, which ultimately speciated as Fusarium solani.A blood culture and diagnostic vitrectomy (Figure 3) similarly yielded Fusarium species.His vision remained intact, able to count fingers from two feet in both eyes afterward (Figure 4).Further examination revealed systemic dissemination with the involvement of his skin and several joints, which similarly grew Fusarium species.From the blood sample, amphotericin B was found to have a minimum inhibitory concentration (MIC) of 2 micrograms/mL and voriconazole an MIC of 4 micrograms/mL.
Systemic coverage was initiated with intravenous amphotericin B and voriconazole and, eventually, a novel experimental antifungal, fosmanogepix.Ocular treatment consisted of ten rounds of intravitreal injections every other day with antifungals, alternating between amphotericin B and voriconazole.Examination findings stabilized during treatment, with similar visual acuity and no extension of the lesions.Given extensive systemic disease, the patient ultimately wished to discontinue local treatments and withdrew care, succumbing to his disease process.Due to concern for recurrent or widespread malignancy, magnetic resonance imaging (Figure 2) and a lumbar puncture were performed, neither of which showed evidence of neoplasia.The patient received a vitreous tap and intravitreal injection of voriconazole (100 mg/0.1 mL), vancomycin (1 mg/0.1 mL), and ceftazidime (2.25 mg/0.1 mL) in both eyes.After five days, the culture began to grow fungi, which ultimately speciated as Fusarium solani.A blood culture and diagnostic vitrectomy (Figure 3) similarly yielded Fusarium species.His vision remained intact, able to count fingers from two feet in both eyes afterward (Figure 4).Further examination revealed systemic dissemination with the involvement of his skin and several joints, which similarly grew Fusarium species.From the blood sample, amphotericin B was found to have a minimum inhibitory concentration (MIC) of 2 micrograms/mL and voriconazole an MIC of 4 mg/mL.Systemic coverage was initiated with intravenous amphotericin B and voriconazole and, eventually, a novel experimental antifungal, fosmanogepix.Ocular treatment consisted of ten rounds of intravitreal injections every other day with antifungals, alternating between amphotericin B and voriconazole.Examination findings stabilized during treatment, with similar visual acuity and no extension of the lesions.Given extensive systemic disease, the patient ultimately wished to discontinue local treatments and withdrew care, succumbing to his disease process.

Discussion
Even with aggressive systemic and local therapy, fungal endophthalmitis can be a devastating disease with a poor visual prognosis.Fungal endophthalmitis more often occurs exogenously after trauma, keratitis, or intraocular surgery; endogenous endophthalmitis associated with systemic fungal infection represent 2-15% of all cases [6].The most common organisms found in endogenous fungal endophthalmitis are Candida albicans and Aspergillus species [7].Here, we present a case of bilateral endogenous fungal endophthalmitis caused by Fusarium solani, which is a rare presentation with isolated case reports in the literature, as summarized below.

Literature Review
Twelve species of Fusarium have been reported to be associated with systemic infection, of which the most common are Fusarium solani (~50% of cases), Fusarium oxysporum (~20% of cases), Fusarium verticillioidis (~10% of cases) and Fusarium monoliforme (~10% of cases) [1].When associated with ocular infection, Fusarium species are more often associated with keratitis and exogenous endophthalmitis [1,6].
A literature review was conducted on April 10, 2024, on PubMed using the keywords "fusarium endophthalmitis" and "endogenous fusarium endophthalmitis."All cases of endogenous Fusarium endophthalmitis referred to in these articles were also included.Several larger case series reported exogenous Fusarium endophthalmitis, while a limited number of case reports associated with endogenous Fusarium endophthalmitis were found (n = 30, not including the case reported here).Prior to this review, the largest case series included 14 cases [8], so this is the most comprehensive literature review to our knowledge to date.The results are summarized in Table 1.
Treatment options for fungal endophthalmitis include topical natamycin (though not often used alone), intravitreal injections of antifungals such as amphotericin B (5-10 µg/0.1 mL) and voriconazole (1 mg/0.1 mL), systemic oral or intravenous antifungal treatment with amphotericin B, and surgical treatment with pars plana vitrectomy (n = 17/31) or the removal of other infected areas (e.g., lensectomy) (n = 4/31) and in recalcitrant cases, evisceration or enucleation (n = 7/31).Almost all authors used systemic amphotericin (n = 24/31) and/or an azole (n = 14/31) such as voriconazole (most common, n = 12), fluconazole (n = 1), or itraconazole (n = 1).Intravitreal injections of amphotericin only (n = 10/31), vorizonacole only (n = 6/31), or an alternating combination of amphotericin and voriconazole (n = 6/31) were given at most, simultaneously and once weekly, up to 6 weeks [20] (aside from the reported case).Seven cases received systemic therapy without intravitreal injections, with one of these patients undergoing pars plana vitrectomy and one requiring enucleation.No well-studied regimen exists to guide treatment selection, and most cases used combination therapy.Vitrectomy provides the advantage of reducing the fungal burden in the vitreous and provides additional samples for establishing the diagnosis, as well as addressing common post-infectious sequelae such as retinal detachment and epiretinal membrane [21].In one case of fungal endophthalmitis (not specified to be Fusarium), the intralesional injection of voriconazole and povidone-iodine was performed with final vision at 20/25 [22].
Systemic outcome and final vision varied without a consistent pattern.Two cases had patients that ultimately recovered to 20/20 visual acuity; both of these cases involved only the eye and suggested the importance of immune recovery and treatment with vitrectomy, systemic amphotericin B, and intravitreal injections of antifungals [16,20].Overall, this literature review suggests the need for aggressive treatment and a surgical reduction in disease burden, but no conclusion can be drawn about the most effective treatment nor about systemic and ocular prognosis upon diagnosis.Only three patients had final visual acuities between 20/50 and 20/80, while most patients experienced near or total vision loss of the affected eyes [8,17,23].Multi-system Fusarium involvement (n = 21/31) resulted in both survival (n = 11 of 24 with reported systemic outcomes) and death (n = 13 of 24 with reported systemic outcomes), likely in part related to factors involved in the course of their systemic disease.Abbreviations: AML, acute myeloid leukemia; AmB, Amphotericin B; 5-FC, 5-fluorocytosine; ALL, acute lymphocytic leukemia; BMT, bone marrow transplant; HSCT, hematopoietic stem cell transplant; HL, Hodgkin lymphoma; AIDS, Acquired immunodeficiency syndrome; AmB, Amphotericin B; Vori, voriconazole; NA, not available/applicable; RD, retinal detachment; PK, penetrating keratoplasty.

Figure 1 .
Figure 1.B-scan ultrasonography of macular lesions in the left eye on initial examination demonstrated vitreous opacities consistent with vitritis, elevated subretinal lesions, and a thickened choroid.

Figure 1 .
Figure 1.B-scan ultrasonography of macular lesions in the left eye on initial examination demonstrated vitreous opacities consistent with vitritis, elevated subretinal lesions, and a thickened choroid.

Figure 2 .
Figure 2. Magnetic resonance imaging of the brain and orbit at the time of initial diagnosis showed abnormal thickening of the left sclera and periorbital soft tissues but no lesions infiltrating the optic nerve to suggest malignancy.

Figure 2 .
Figure 2. Magnetic resonance imaging of the brain and orbit at the time of initial diagnosis showed abnormal thickening of the left sclera and periorbital soft tissues but no lesions infiltrating the optic nerve to suggest malignancy.

Figure 2 .
Figure 2. Magnetic resonance imaging of the brain and orbit at the time of initial diagnosis showed abnormal thickening of the left sclera and periorbital soft tissues but no lesions infiltrating the optic nerve to suggest malignancy.

Figure 3 .
Figure 3. (a) View of vitritis and subretinal lesions in the right eye during diagnostic vitrectomy and prior to core vitrectomy.(b) View of subretinal lesions in the right eye during diagnostic vitrectomy and after core vitrectomy.

Figure 4 .Figure 3 .
Figure 4. (a) Right eye post-operative day 2 after diagnostic vitrectomy of the right eye.(b) The left eye on the same day.

Figure 2 .
Figure 2. Magnetic resonance imaging of the brain and orbit at the time of initial diagnosis showed abnormal thickening of the left sclera and periorbital soft tissues but no lesions infiltrating the optic nerve to suggest malignancy.

Figure 3 .
Figure 3. (a) View of vitritis and subretinal lesions in the right eye during diagnostic vitrectomy and prior to core vitrectomy.(b) View of subretinal lesions in the right eye during diagnostic vitrectomy and after core vitrectomy.

Figure 4 .Figure 4 .
Figure 4. (a) Right eye post-operative day 2 after diagnostic vitrectomy of the right eye.(b) The left eye on the same day.